Preeclamptic (PE) placental beds are characterized by a disordered trophoblast invasion of the decidual spiral arterioles and a marked mononuclear cell infiltrate comparable to that seen in a vascular transplant rejection. Expression and recognition of HLA antigens are critical for cell-cell interactions such as these. Current evidence indicates that most trophoblast populations have reduced to no expression of HLA antigens, and this appears to be a key reason for placental survival within an immunocompetent mother. We have recently shown that this process is under gene regulation and can indeed by up regulated by such stimuli as gamma interferon. Our current studies indicate that these genes are dysregulated in preeclamptic placentas. In this proposal HLA antigen (immunohistochemistry) and gene expression (mRNA levels) will be contrasted in normal and PE placentas and placental bed biopsies. Secondly factors important for regulating of MHC antigen expression in trophoblasts will be identified utilizing in vitro systems for growing isolated trophoblasts. Known inducers and inhibitors such as prostaglandins, AFP, and corticosteroids will be examined. In addition, we will establish whether the placenta produces its own inhibitor of HLA expression. Basic mechanism(s) of regulation of HLA expression in normal and PE will be investigated by examining the degree of methylation of DNA regulatory regions using Southern blotting. In addition, we will establish whether HLA antigen expression is regulated by antigen shedding. Thus, we will greatly increase our knowledge of the process of HLA gene regulation in trophoblasts and will be able to establish whether disordered regulation is responsible for or characteristic of PE.